Smoking and affective function are closely intertwined and considerable research suggests that dysregulated affect is a primary factor in the maintenance of, and relapse to smoking. Smokers frequently cite withdrawal-induced negative affect (NA) as a primary factor for re-initiating smoking (i.e. smoking lapse). This is significant given that lapses are one of the best predictors of full-blown relapse. Smokers with major depressive disorder (MDD) smoke at significantly higher rates, report greater NA during abstinence and are at greater risk for relapse than non-depressed (ND) individuals. Although considerable work has been conducted to characterize the association between dysregulated affect and smoking among MDD and ND individuals, little work has focused on the neural bases of this association, and to our knowledge, no reported work has focused on the effects of smoking and depression on the ability to regulate affective processes (i.e. emotion regulation [ER]). Recently, we have demonstrated that smoking abstinence disrupts emotional function via its impact on frontal executive function. Moreover, this modulation appears to be greater among smokers with elevated depressive symptoms. Whereas those data provide novel insights into the role of withdrawal on emotional reactivity, they fail to inform the neural basis of smoking-depression comorbidity and their interactive effects on the proactive regulation of emotion. Identifying smoking-depression effects on ER is critical for understanding self-regulation failure in the context of addiction and mental illness. In addition, though increased NA precipitates smoking relapse, associations between ER and smoking relapse remain unknown. Therefore, the goal of this application is to use affective neuroscience to investigate the effects of smoking and depression on ER, and their interaction with smoking behavior. Our overarching hypothesis is that smoking abstinence will disrupt ER via its impact on frontal executive function and that depression will worsen the effects. Furthermore, we hypothesize that ER failure will be associated with smoking lapse behavior as modeled in the laboratory. Dependent smokers (n=60) with and without MDD will be scanned during an ER task on two occasions: smoking as usual, and 24hrs abstinent. A nonsmoker control group with and without MDD will also be scanned on two occasions. On a separate visit, NS and ABS smokers will receive a monetary reinforcement to perform the ER task, and for smokers, resist the opportunity to smoke ad lib. The proposed research is significant as it will shed new light on the neural mechanisms that govern associations between depression and smoking. Despite known and costly associations between these factors, little is known regarding their co-occurrence and such information will provide a foundation for the development of novel and more effective interventions. For instance, support for our hypotheses will guide the rationale development of targeted interventions for disrupted emotional information processing in smokers using neural stimulation (rTMS), behavioral (CBT) and/or pharmacologic techniques. PUBLIC HEALTH RELEVANCE: Cigarette smoking is the leading preventable cause of death and disability in the U.S. and individuals with elevated depression symptoms or clinically diagnosed major depressive disorder (MDD) smoke at significantly higher rates than non-depressed individuals. Elevated negative affect and affective dysregulated emotional control may contribute to greater smoking among individuals with MDD. The proposed research will shed new light on the neural mechanisms that govern associations between depression and smoking. Despite known and costly associations between these factors, little is known regarding their co-occurrence and such information will provide a foundation for the development of novel and more effective interventions. For instance, support for our hypotheses will guide the development of targeted interventions for disrupted emotional information processing in high depression individuals with neural stimulation (rTMS), behavioral (CBT) and/or pharmacologic techniques.